The scaffold protein p140Cap limits ERBB2-mediated breast cancer progression interfering with Rac GTPase-controlled circuitries

Silvia Grasso, Jennifer Chapelle, Vincenzo Salemme, Simona Aramu, Isabella Russo, Nicoletta Vitale, Ludovica Verdun di Cantogno, Katiuscia Dallaglio, Isabella Castellano, Augusto Amici, Giorgia Centonze, Nanaocha Sharma, Serena Lunardi, Sara Cabodi, Federica Cavallo, Alessia Lamolinara, Lorenzo Stramucci, Enrico Moiso, Paolo Provero, Adriana AlbiniAnna Sapino, Johan Staaf, Pier Paolo Di Fiore, Giovanni Bertalot, Salvatore Pece, Daniela Tosoni, Stefano Confalonieri, Manuela Iezzi, Paola Di Stefano, Emilia Turco, Paola Defilippi

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Abstract

The docking protein p140Cap negatively regulates tumour cell features. Its relevance on breast cancer patient survival, as well as its ability to counteract relevant cancer signalling pathways, are not fully understood. Here we report that in patients with ERBB2-amplified breast cancer, a p140Cap-positive status associates with a significantly lower probability of developing a distant event, and a clear difference in survival. p140Cap dampens ERBB2-positive tumour cell progression, impairing tumour onset and growth in the NeuT mouse model, and counteracting epithelial mesenchymal transition, resulting in decreased metastasis formation. One major mechanism is the ability of p140Cap to interfere with ERBB2-dependent activation of Rac GTPase-controlled circuitries. Our findings point to a specific role of p140Cap in curbing the aggressiveness of ERBB2-amplified breast cancers and suggest that, due to its ability to impinge on specific molecular pathways, p140Cap may represent a predictive biomarker of response to targeted anti-ERBB2 therapies.

Original languageEnglish
Pages (from-to)14797
JournalNature Communications
Volume8
DOIs
Publication statusPublished - Mar 16 2017

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Grasso, S., Chapelle, J., Salemme, V., Aramu, S., Russo, I., Vitale, N., Verdun di Cantogno, L., Dallaglio, K., Castellano, I., Amici, A., Centonze, G., Sharma, N., Lunardi, S., Cabodi, S., Cavallo, F., Lamolinara, A., Stramucci, L., Moiso, E., Provero, P., ... Defilippi, P. (2017). The scaffold protein p140Cap limits ERBB2-mediated breast cancer progression interfering with Rac GTPase-controlled circuitries. Nature Communications, 8, 14797. https://doi.org/10.1038/ncomms14797